tbuckley/cabot-search huggingface dataset:
Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors
Authors: Sarah Dybowski, Sebastian Torke, Martin S. Weber
Journal: JAMA Neurology (2023)

Importance Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell–depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell–directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK). Observations BTK is centrally involved in the B cell receptor–mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety. Conclusions and Relevance While the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.
Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA
Authors: Peter Anderson, Maurizio Ghisoli, Brian D. Crompton, Kelly S. Klega, Leonard H. Wexler, Emily K. Slotkin, Laura Stanbery, Luisa Manning, Gladice Wallraven, Meghan Manley, Staci Horvath, Ernest Bognar, John Nemunaitis
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment. Patients and Methods: In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106–107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples. Results: Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6–46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3–NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden. Conclusions: Results demonstrated safety of combination Vigil/TEM/IRI.
Incidence, Risk, and Severity of SARS-CoV-2 Reinfections in Children and Adolescents Between March 2020 and July 2022 in Serbia
Authors: Snežana Medić, Cleo Anastassopoulou, Zagorka Lozanov-Crvenković, Nataša Dragnić, Vladimir Petrović, Mioljub Ristić, Tatjana Pustahija, Athanasios Tsakris, John P. A. Ioannidis
Journal: JAMA Network Open (2023)

During the COVID-19 pandemic, children and adolescents were massively infected worldwide. In 2022, reinfections became a main feature of the endemic phase of SARS-CoV-2, so it is important to understand the epidemiology and clinical impact of reinfections.To assess the incidence, risk, and severity of pediatric SARS-CoV-2 reinfection.This retrospective cohort study used epidemiologic data of documented SARS-CoV-2 infections from the surveillance database of the Institute for Public Health of Vojvodina. A total of 32 524 children and adolescents from Vojvodina, Serbia, with laboratory-confirmed SARS-CoV-2 infection between March 6, 2020, and April 30, 2022, were followed up for reinfection until July 31, 2022.Incidence rates of documented SARS-CoV-2 reinfection per 1000 person-months, estimated risk of documented reinfection 90 days or more after laboratory confirmation of primary infection, reinfection severity, hospitalizations, and deaths.The study cohort included 32 524 children and adolescents with COVID-19 (mean [SD] age, 11.2 [4.9] years; 15 953 [49.1%] male), including 964 children (3.0%) who experienced documented reinfection. The incidence rate of documented reinfections was 3.2 (95% CI, 3.0-3.4) cases per 1000 person-months and was highest in adolescents aged 12 to 17 years (3.4; 95% CI, 3.2-3.7). Most reinfections (905 [93.9%]) were recorded in 2022. The cumulative reinfection risk was 1.3% at 6 months, 1.9% at 9 months, 4.0% at 12 months, 6.7% at 15 months, 7.2% at 18 months, and 7.9% after 21 months. Pediatric COVID-19 cases were generally mild. The proportion of severe clinical forms decreased from 14 (1.4%) in initial episodes to 3 (0.3%) in reinfections. Reinfected children were approximately 5 times less likely to have severe disease during reinfection compared with initial infection (McNemar odds ratio, 0.2; 95% CI, 0.0-0.8). Pediatric reinfections rarely led to hospitalization (0.5% vs 1.3% during primary infections), and none resulted in death.This cohort study found that the SARS-CoV-2 reinfection risk remained substantially lower for children and adolescents compared with adults as of July 2022. Pediatric infections were mild, and reinfections were even milder than primary infections.
Prevalence and Incidence of Atrial Fibrillation Among Older Primary Care Patients
Authors: Shaan Khurshid, Jeffrey M. Ashburner, Patrick T. Ellinor, David D. McManus, Steven J. Atlas, Daniel E. Singer, Steven A. Lubitz
Journal: JAMA Network Open (2023)

This cohort study is a secondary analysis of the VITAL-AF trial and assesses the prevalence and incidence of atrial fibrillation among the trial’s control participants.
Comparison of Distal Radius Fracture Outcomes in Older Adults Stratified by Chronologic vs Physiologic Age Managed With Casting vs Surgery
Authors: Mayank Jayaram, Hao Wu, Alfred P. Yoon, Robert L. Kane, Lu Wang, Kevin C. Chung
Journal: JAMA Network Open (2023)

Importance Casting is recommended for adults older than 65 years with distal radius fractures (DRFs) because similar long-term outcomes are achieved regardless of treatment. However, physiologically younger adults could benefit from operative DRF management despite advanced chronologic age. Objective To examine how chronologic age compares with measures of physiologic age in DRF treatment recovery. Design, Setting, and Participants This retrospective secondary analysis of the Wrist and Radius Injury Surgical Trial (WRIST) was performed from May 1 to August 31, 2022. WRIST was a 24-center randomized clinical trial that enrolled participants older than 60 years with unstable DRFs from April 1, 2012, to December 31, 2016. Interventions Participants selected casting or surgery. Patients who selected surgery were randomly assigned to volar lock plating, percutaneous pinning, or external fixation. Participants were stratified by chronologic age, number of comorbidities, and activity status. Main Outcomes and Measures The primary outcome was Michigan Hand Outcomes Questionnaire (MHQ) score assessed at 6 weeks, 3 months, 6 months, and 1 year. Partial correlation (PC) analysis adjusted for confounding. Results The final cohort consisted of 293 participants (mean [SD] age, 71.1 [8.89] years; 255 [87%] female; 247 [85%] White), with 109 receiving casting and 184 receiving surgery. Increased chronologic age was associated with increased MHQ scores in the surgery group at all time points but decreased MHQ scores in the casting group at 12 months (mean [SD] score, −0.46 [0.21]; P = .03). High activity was associated with improved MHQ scores in the surgical cohort at 6 weeks (mean [SD] score, 12.21 [5.18]; PC = 0.27; P = .02) and 12 months (mean [SD] score, 13.25 [5.77]; PC = 0.17; P = .02). Comorbidities were associated with decreased MHQ scores at all time points in the casting group. Clinically significant differences in MHQ scores were associated with low physical activity, 4 or more comorbidities, or increased age by 15 years. Conclusions and Relevance In this retrospective secondary analysis of WRIST, chronologic age was not associated with functional demand. These findings suggest that physicians should counsel active older adults with few comorbidities on earlier return to daily activities after surgery compared with casting. Trial Registration ClinicalTrials.gov Identifier: NCT01589692
State-Level Indicators of Childhood Educational Quality and Incident Dementia in Older Black and White Adults
Authors: Yenee Soh, Rachel A. Whitmer, Elizabeth Rose Mayeda, M. Maria Glymour, Rachel L. Peterson, Chloe W. Eng, Charles P. Quesenberry, Jennifer J. Manly, Paola Gilsanz
Journal: JAMA Neurology (2023)

Importance Higher educational attainment is associated with reduced dementia risk, but the role of educational quality is understudied, presenting a major evidence gap, especially as it may contribute to racial inequities. Objective To evaluate the association between state-level educational quality during childhood and dementia risk. Design, Setting, and Participants This cohort study analyzed longitudinal data collected from January 1, 1997, through December 31, 2019 (23-year follow-up period). The sample comprised members of Kaiser Permanente Northern California (KPNC), a large integrated health care delivery system, who completed an optional survey during 1964-1972. Eligible individuals were US born; non-Hispanic Black or non-Hispanic White; aged 65 years or older as of January 1, 1996; were still alive; and did not have a dementia diagnosis or lapse in KPNC membership greater than 90 days between January 1 and December 31, 1996. Exposures Historical state-level administrative indicators of school quality (school term length, student-teacher ratio, and attendance rates) linked to participants using birth state and birth year (with a 6-year lag) and divided into tertiles using the pooled sample. Main Outcomes and Measures Dementia diagnoses from electronic health records between 1997 and 2019 were analyzed between March 1 and August 31, 2022. The associations of educational quality with incident dementia were estimated using Cox proportional hazards regression models. Results Among 21 450 KPNC members who participated in the optional survey, individuals born before availability of educational quality records (n = 87) and missing educational attainment (n = 585) were excluded. The final analytic sample was 20 778 individuals (56.5% women, 43.5% men; mean [SD] age, 74.7 [6.5] years; 18.8% Black; 81.2% White; 41.0% with less than high school education). Among Black individuals, 76.2% to 86.1% (vs 20.8%-23.3% of White individuals) attended schools in states in the lowest educational quality tertiles. Highest (vs lowest) educational quality tertiles were associated with lower dementia risk (student-teacher ratio: hazard ratio [HR], 0.88 [95% CI, 0.83-0.94]; attendance rates: HR, 0.80 [95% CI, 0.73-0.88]; term length: HR, 0.79 [95% CI, 0.73-0.86]). Effect estimates did not differ by race and were not attenuated by adjustment for educational attainment. Conclusions and Relevance In this cohort study, lower state-average educational quality was more common among Black individuals and associated with higher dementia risk. Differential investment in high-quality education due to structural racism may contribute to dementia disparities.
Access to gene therapy for rare diseases when commercialization is not fit for purpose
Authors: Thomas Fox, Juan Bueren, Fabio Candotti, Alain Fischer, Alessandro Aiuti, Arjan Lankester, Michael Albert, Maria Ester Bernardo, Marina Cavazzana, Stephan Ehl, Benedicte Neven, Johan Prevot, Axel Schambach, Julian Sevilla, Adrian Thrasher, Rob Wynn, Claire Booth
Journal: Nature Medicine (2023)
Equitable Policies and Center-Level Commitment May Be Associated With Improved Access to Kidney Transplantation for Undocumented Immigrants
Authors: Aaron M. Delman, Shimul A. Shah, Madison C. Cuffy
Journal: JAMA Network Open (2023)

Natsuki Eguchi, BS; Ekamol Tantisattamo, MD, MPH; Dean Chung, BS; Uttam G. Reddy, MD; Antoney Ferrey, MD; Donald Dafoe, MD; Hirohito Ichii, MD, PhD
Race and the 2022 American Academy of Pediatrics Hyperbilirubinemia Guideline—Reply
Authors: Sharon Ostfeld-Johns, Elena Aragona, Louis Hart
Journal: JAMA Pediatrics (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Race and the 2022 American Academy of Pediatrics Hyperbilirubinemia Guideline
Authors: Alex R. Kemper, Thomas B. Newman, Joseph L. Wright
Journal: JAMA Pediatrics (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Maternal Outcomes Among Pregnant Women With Congenital Heart Disease–Associated Pulmonary Hypertension
Authors: Qian Zhang, Fang Zhu, Guocheng Shi, Chen Hu, Weituo Zhang, Puzhen Huang, Chunfeng Zhu, Hong Gu, Dong Yang, Qiangqiang Li, Yonghua Niu, Hao Chen, Ruixiang Ma, Ziyi Pan, Huixian Miao, Xin Zhang, Genxia Li, Yabing Tang, Guyuan Qiao, Yichen Yan, Zhongqun Zhu, Hao Zhang, Fengzhen Han, Yanna Li, Jianhua Lin, Huiwen Chen
Journal: Circulation (2023)

Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH.
Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance
Authors: Juanjuan Yang, Dake Song, Bingqian Li, Xiaoxiao Gao, Yuetong Wang, Xiaohu Li, Changshun Bao, Caijiao Wu, Yu Bao, Samuel Waxman, Guoliang Chen, Yongkui Jing
Journal: Drug Resistance Updates (2023)
Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation
Authors: Rachel Naomi Curry, Isamu Aiba, Jochen Meyer, Brittney Lozzi, Yeunjung Ko, Malcolm Ford McDonald, Anna Rosenbaum, Alexis Cervantes, Emmet Huang-Hobbs, Carolina Cocito, Jeffrey Peter Greenfield, Ali Jalali, Jay Gavvala, Carrie Mohila, Akdes Serin Harmanci, Jeffrey Noebels, Ganesh Rao, Benjamin Deneen
Journal: Neuron (2023)
Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis
Authors: Chiahsuan Chin, Ranjithkumar Ravichandran, Kristina Sanborn, Timothy Fleming, Stephen B. Wheatcroft, Mark T. Kearney, Sofya Tokman, Rajat Walia, Michael A. Smith, David J. Flint, Thalachallour Mohanakumar, Ross M. Bremner, Angara Sureshbabu
Journal: Cell Reports Medicine (2023)

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.
A machine-learning algorithm integrating baseline serum proteomic signatures predicts exercise responsiveness in overweight males with prediabetes
Authors: Candela Diaz-Canestro, Jiarui Chen, Yan Liu, Hao Han, Yao Wang, Eric Honoré, Chi-Ho Lee, Karen S.L. Lam, Michael Andrew Tse, Aimin Xu
Journal: Cell Reports Medicine (2023)

The molecular transducers conferring the benefits of chronic exercise in diabetes prevention remain to be comprehensively investigated. Herein, serum proteomic profiling of 688 inflammatory and metabolic biomarkers in 36 medication-naive overweight and obese men with prediabetes reveals hundreds of exercise-responsive proteins modulated by 12-week high-intensity interval exercise training, including regulators of metabolism, cardiovascular system, inflammation, and apoptosis. Strong associations are found between proteins involved in gastro-intestinal mucosal immunity and metabolic outcomes. Exercise-induced changes in trefoil factor 2 (TFF2) are associated with changes in insulin resistance and fasting insulin, whereas baseline levels of the pancreatic secretory granule membrane major glycoprotein GP2 are related to changes in fasting glucose and glucose tolerance. A hybrid set of 23 proteins including TFF2 are differentially altered in exercise responders and non-responders. Furthermore, a machine-learning algorithm integrating baseline proteomic signatures accurately predicts individualized metabolic responsiveness to exercise training.
Brief synaptic inhibition persistently interrupts firing of fast-spiking interneurons
Authors: Simon Chamberland, Erica R. Nebet, Manuel Valero, Monica Hanani, Robert Egger, Samantha B. Larsen, Katherine W. Eyring, György Buzsáki, Richard W. Tsien
Journal: Neuron (2023)

Neurons perform input-output operations that integrate synaptic inputs with intrinsic electrical properties; these operations are generally constrained by the brevity of synaptic events. Here, we report that sustained firing of CA1 hippocampal fast-spiking parvalbumin-expressing interneurons (PV-INs) can be persistently interrupted for several hundred milliseconds following brief GABA
Emerging treatments for myelodysplastic syndromes: Biological rationales and clinical translation
Authors: Juan Jose Rodriguez-Sevilla, Vera Adema, Guillermo Garcia-Manero, Simona Colla
Journal: Cell Reports Medicine (2023)

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients' only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS pathogenesis has enabled the development of new agents that target molecular alterations, cell death regulators, signaling pathways, and immune regulatory proteins in MDS. Here, we review novel therapies for patients with MDS in whom HMA therapy has failed, with an emphasis on the biological rationale for these therapies' development.